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Physiologic Autoimmunity and

Preventive Medicine
Edited By
Alexander B. Poletaev
Medical Research Center “Immunculus”
Moscow
Russia
CONTENTS
Foreword i
Preface viii
List of Contributors xii
CHAPTERS
1. The Main Principles of Adaptive Immune System Function: Self-
Recognition, Self-Interaction, and Self-Maintenance 3
Alexander B. Poletaev
2. The Integrative (Co-Operative and Defensive) Function of the
Immune System and its Role in Preventive Medicine 21
Zlatko Dembić
3. The Hallmarks of Physiologic Antibody Immunity in Cardiac
Diseases and its Impact to Personalized Medicine 46
Olga M. Moiseeva, D.A. Grigoŕeva and Sergey V. Skurydin
4. Autoimmunity vs. Autoallergy in Immunoneuroendocrine
Regulation and Dysregulation 72
Leonid P. Churilov, Yury I. Stroev and Albert Sh. Zaichik
5. Autoimmune Phenomena through the View of Predictive,
Preventive and Personalized Medicine 167
Anastasiya Putintseva, Sergey Krynskii, Mariya Bocharova, Anna
Andreeva, Mathew von Herrath, Dmitrii Kostyshev, Iliya Kurguzov,
Paul Muchowski, Artem Kostyakov, Michail Paltsev and Sergey
Suchkov
6. Autoantibodies: Serum Content or Profiles? 199
Alexander B. Poletaev
7. Autoimmune Thyroiditis: A New Comorbidity of the Most
Prevalent Endocrine Disease, Its Prevention and Prediction 208
Leonid P. Churilov, Yury I. Stroev, Irina Yu. Serdyuk and Oksana M.
Mudzhikova
Index 234
i
FOREWORD
FEW WORDS ABOUT PREVENTIVE MEDICINE
The prediction and prevention are not a field for scholastic speculations,
but concrete activity on preserving of human health and active longevity
According to the Bible, Noah's grandfather, Methuselah lived 969 years. It is
easier to believe and accept that, by calculations of gerontologists, the biological
resource of a human body lasts for not less than 120 years. The well-known
medieval physician Paracelsus considered that the person could live 600 years.
Haller and Hufeland (XVIII century) limited human life age to 200 years. Ilya
Mechnikov and Alexander Bogomolets talked about 160 years. But how many
people will live at least 100 years, do you know?
The fact that the overwhelming majority of us do not live 60-80 years until our
biological limit characterizes pessimistically contemporary state of medicine,
nobody knows why, called “public healthcare”. The modern medicine (in a
traditional Western variant) does not protect human health or, otherwise, talk
round corners. The modern medicine is the medicine of “repair”, the medicine of
tablets and a scalpel. This is not the fault made by healthcare policy makers, or by
physicians. It historically determined. The basic paradigm of medical aid
involuntarily formed throughout many centuries.
Today “the repair medicine” also includes such a significant segment like disaster
medicine and military medicine. However, it is rather a small segment of
contemporary medicine, which focused not on wounds, traumas or life-
threatening infections, but on chronic and slowly developing cardiovascular,
malignant, endocrine, neurological, and other diseases. Understanding of the crisis
in the current healthcare situation is an incentive to reflect on alternative ways of
the development of medicine, or rather, about the formation of a real healthcare -
medicine of prevention.
It is worth saying that “tablet strategy” practically exhausted. Today the average
investment for one pharmaceutical compound from its development to market
ii
launch requires more than 1 billion dollars. Thus, not only practical physicians,
but also pharmacologists recognize that “tablet strategy” is effective in not more
than 30% of cases maximum. Some specialists consider that the inefficiency or
the harmfulness of pharmaceuticals reaches 85% (from the lecture by Vitaly
Prutsky, the Head of Information Management in R&D “AstraZeneca” in Russia
and Eastern Europe, 2012).
It is interesting that captain Jacques Margeret employed to tsar Boris Godunov
wrote in his book titled “Estat de l'empire de Russie, et grande duche de
Moscovie” dated 1606, “Many Russians live until 90-100 and 120 years and face
illnesses only in an old age. Thus, nobody accepts medicines with the exception of
the tsar and top noblemen”.
So the way of healthcare development surely guides ours society to a deadlock.
What shall we do?
PREVENTIVE MEDICINE IDEA
The preventive medicine (PM) is an alternative healthcare ideology and
methodology. Its essence refers to the personified management of physiological
health state and organism reserves. The main objective is the high-grade healthy
human life prolongation up to natural, biologically restricted limits. The main task
is to not to cure illnesses, but to reveal any deviations of organism to lead to
diseases and take the targeted actions to prevent illnesses.
The philosophy of the preventive medicine differs essentially from the traditional
Western medicine philosophy so long as it based not on the paradigm of “repair”
but maintenance managing of the human health.
We consider that in order to solve today’s and tomorrow’s acute demographic
problems along with the healthy birthrate ensuring, the morbidity and mortality
decrease, the high-grade healthy and efficient life prolongation it is necessary, not
in words, but in practice, to get down to the PM concept formation and to the
practical step development for its implementation.
iii
PRACTICAL IMPLEMENTATION OF PM CONCEPTION AS A
CHALLENGE FOR STATE AND GOVERNMENT
The task includes the creation of new technologies and techniques, and their
application in the clinical practice, the management system construction for
mutual relations between citizens, medical organizations, companies, institutions,
and the state regulating or supervisory agencies involved in the medical service
sector.
It is necessary to adjust the activity range for different organs in state
management, education, fundamental science, clinical practice, and medical
business. The task complexity requires the construction of optimal connective
trajectories (profiles) between a considerable quantity of dotted interdisciplinary
and interdisciplinary competences.
In our opinion, the decision of such a global problem is quite possible nowadays
with the help of “Strategy Project Principle” for the development and
implementation of the predictive and preventive medical technologies and
practices as strategic management models.
We consider necessary to accept from the first steps not separate techniques, but
complete concept project with 15-30 year planning horizon. It will allow revise
and manage simultaneously the whole cycle of healthcare development. This
conception will be capable to be changed and developed in time in accordance
with current events and circumstances. The project principal offered by us ensures
the management system from the moment of the innovative mainstream,
formation or scientific idea appearance until the moment of rendering high
qualitative certificated healthcare service for each concrete person.
We suppose practical fulfillment of PM project should include the following basic
sections:
1. Organizational, technical and personnel support; the solving of
vocational training issues for highly qualified professional specialists
in close inter/interdisciplinary sectors (physicians, researchers,
viii
PREFACE
Historically immunology formed as a branch of applied microbiology and
generations of specialists in immunology educated by microbiologists. Therefore,
“microbiological” points of view concerning predestination of the Immune
System (ISYS) reproduced for decades. Essence of such views may be impressed
by the phrase: the main function of the ISYS (or for precision – Adaptive Immune
System) is the constant struggle against any non-selfness which gets into the host-
organism (foreign antigens in microbes, cells, or particles).
This position does not permit to answer a lot of questions. For example:
1. Why ISYS is not struggling against numerous representatives of the
“normal” microflora?
2. Why ISYS is not fighting against thousands paternal antigens
expressed fetus?
3. If antigens which had not been presented to ISYS during early
ontogenesis should be considered as non-self antigens, why ISYS
does not reject the lactating breast expressing a lot of milk’ neo-
antigens?
4. If the main function of the ISYS is the constant struggle why and
how ISYS is involving in maintenance of general homeostasis, in
regulation of tissue growth, reparation, and differentiation, in general
morphogenesis and fetal development?
5. If any of autoreactivity is the sign of pathology, why autoantibodies
and self-reactive lymphocytes presented in each healthy individual
during all lifespan?
6. Restricted (microbiological) view about immunity has become a
touchable obstacle now for practical introduction some new ideas and
methods, related to pre-nosologic detection of different chronic
diseases.
ix
These and other “difficult questions” have been considered in the eBook. An
attempt to take a look upon immunity from an unusual angle, and re-evaluate the
biological meaning of the immune system from physiological point of view
undertaken.
It is especially important: if we have to consider the immunity-autoimmunity
phenomena from the position of physiology (see Chapter 1) – it automatically
gives us a new ground for real construction of amazing building of future
individualized prognostic-&-preventive medicine. Appropriately authors of each
chapter of the eBook have to do somehow with the subject.
Let us touch the idea of preventive medicine shortly. It is well known that ancient
Greek’s God of treatment, Asclepius had two daughters – Panacea (Πανάκεια,
Panakeia) – she was able to treat any disease – and Hygieia, Ὑγιεία or Hygēa (she
was able to prevent any disease). According to the legend some ancient Chinese
doctors had received their salary only if their patients – members of Emperor’s
family – were healthy, and be deprived if patients were ill. Thereby the idea of
preventive medicine should not be considered only as fashionable trend of recent
years. But in spite of the long history this idea remains an idea, and the main
occupation of modern medicine, as well as centuries ago, is not prevention but
treatment of manifesting diseases. This state is directly related to inability for
ordinary physician to peep into the future of observed patient and to forecast the
future disease absent now.
Do consider the typical sequence of main blocks of events leading to the disease.
1) Influence of factors/agents which may become the trigger of the
disease in some conditions (will be or not potentially hazard factors
initiate the disease partially related to the features of individual
genotype, intensity and duration of action),
2) Compensated (pre-disease) but steady changes on the molecular level,
3) Compensated (pre-disease) but steady functional changes on level of
cells populations,
x
4) Compensated (pre-disease) but steady morphological (structural)
changes on level of cells populations,
5) Partially compensated functional and morphological changes on level
of tissue/organ (first signs of the disease)
6) Stages of functional decompensation – clinically developed disease
7) Recovery with more or less full rehabilitation, or death
These stages clearly indicate for evident necessity to reveal and evaluate some
defined molecular changes (the Stage-2) for maximally early prediction of high-
probably future disease. While most complicated and precision technologies
revealing of tissue defects may operate at the best from the Stage-4.
Many hopes of practical medicine laying for achievements of molecular genetic
turned to be overestimated, mostly because great influence/contribution of
epigenetic factors in the development of most of the diseases. It is not concern
cohort of monogenic diseases, but total contribution of the lasts in population's
morbidity, and mortality is far below of 1%. Modern genetic methods may be
valuable for the evaluation of probability of heart disease, or diabetes, or epilepsy,
etc., expressed as individual risk level above or below of an average. However,
the development of disease and the risk of disease are not considered adequate.
On the other hand, there are molecules-markers (biomarkers). Everybody is aware
of such markers as abnormal blood glucose level, higher bilirubin, or steady
elevated protein in urine, etc. Some biomarkers reflect peculiar changes in the
main systems of the organism and many cases may be more robust and more
certain pre-clinical indicators for the future or presenting disease.
Natural autoantibodies with certain antigen specificity may also be considered as
prognostic useful and universal molecular markers. Steady changes in production
and blood serum content of these molecules have been related directly with tissue
damage of any origin and any location [1], and related to any (not only
“autoimmune”!) presenting now or leading to the development of the disease [2].
xii
List of Contributors
Anna Andreeva, Moscow State Medical & Dentistry University, Moscow,
Russia
Mariya Bocharova, I.M. Sechenov First Moscow State Medical University,
Moscow, Russia
Leonid P. Churilov, Saint Petersburg State University, Faculty of Medicine,
Saint Petersburg, Russia
Zlatko Dembić, Department of Oral Biology, Faculty of Dentistry, University of
Oslo, Norway
Mathew von Herrath, La Jolla Institute for Allergy & Immunology, La Jolla,
CA, USA
Artem Kostyakov, I.M. Sechenov First Moscow State Medical University,
Moscow, Russia
Dmitrii Kostyshev, I.M. Sechenov First Moscow State Medical University,
Moscow, Russia
Sergey Krynskii, I.M. Sechenov First Moscow State Medical University,
Moscow, Russia
Iliya Kurguzov, I.M. Sechenov First Moscow State Medical University,
Moscow, Russia
Olga M. Moiseeva, V.A. Almazov’s Federal Center for Heart, Blood and
Endocrinology, St. Petersburg, Russia
Paul Muchowski, Gladstone Institute of Neurological Disease, UCSF, S-F, CA,
USA
Oksana M. Mudzhikova, Saint Petersburg State University, Faculty of
Medicine, Saint Petersburg, Russia
xiii
Michail Paltsev, National Research Center “Kurchatov Institute”, Moscow,
Russia
Alexander B. Poletaev, The Medical Research Center “Immunculus-Biotest”;
P.K.Anokhin Institute of Normal Physiology, RAMN, Moscow, Russia
Anastasiya Putintseva, I.M. Sechenov First Moscow State Medical University,
Moscow, Russia
Irina Yu. Serdyuk, Saint Petersburg State University, Faculty of Medicine, Saint
Petersburg, Russia
Sergey V. Skurydin, The Medical Research Center “Immunculus-Biotest”,
Moscow, Russia
Yury I. Stroev, Saint Petersburg State University, Faculty of Medicine, Saint
Petersburg, Russia
Sergey Suchkov, I.M. Sechenov First Moscow State Medical University;

The Medical Research Center “Immunculus-Biotest”; P.K.Anokhin Institute of
Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia
Abstract: The immune system is a natural component of and direct participant in the
physiological activity of healthy organisms. The main forms of physiological activity of
the immune system are based on the intrinsic abilities of self-identification, self-
maintenance, self-regulation, and self-reparation – that is, on recognizing components
of the “self”, i.e., natural autoimmunity. The most ancient and homeostatically
important function of natural autoimmunity is autoclearance. A multitude of immune
functions, including those related to antimicrobial defense, derived from the basic
function of autoclearance. Pathological processes of any kind in any organ are usually
accompanied by apoptosis/necrosis of the resident cells and, accordingly, by increased
extracellular concentration of intracellular components. These events induce the
secondary rise in production of autoantibodies with appropriate specificity (opsonines),
which provides augmentation of clearance by facilitating the efficacy of macrophage-
dependent consumption of debris in the affected organ. This phenomenon is sanogenic
in nature and adaptive in essence. Therefore, secondary changes in production and
serum content of tissue-specific autoantibodies can be considered the universal and
earliest detectable marker of any chronic disease.
Keywords: The Immune System, immunophysiology, innate immunity, adaptive
immunity, natural autoimmunity, autoantibodies, immune autoclearance.
THE IMMUNE SYSTEM AND MICROBES
All known eukariotic organisms, from the most primitive forms to the complex
mammals, coexist with a multitude of viruses and bacteria. T- and B-lymphocytes
appeared only at the later stages of evolution—from cartilaginous fishes forward
[1]. Nevertheless, any multicellular organism is in constant contact with
pathogenic microbes, yet effectively resistant to infection, even when lacking an

Department of Oral Biology, Faculty of Dentistry, University of Oslo, PB 1016
Blindern, 0316 Oslo, Norway
Abstract: The goals of preventive medicine from the immunologic perspective should
continue to be aimed at increasing the number of vaccinations against dangerous
infectious diseases and various types of virally-induced cancer. In the future, we can
perhaps hope to find treatments that would prevent rejections of transplanted organs or
even cure autoimmune diseases. These hopes are justified by well-documented research
of immunosuppressive regulatory cells over the past decades. However, the missing link
is the way how we can control them to do what we desire in each clinical setting. So far,
all we therapeutically have is still an unsatisfactory crude “off-switch” for the immune
system in terms of glucocorticoid hormones or other general immunosuppressants. We
need better control at both, the intracellular and extracellular therapeutic levels. The
help might come if we “think” before we try novel therapies. One way how we might
improve planning research and clinical trials would be to see the function of the
immune system from a different perspective. Here I try to help that by discussing
various suggestions about how the immune system works. My suggestion is the
Integrity hypothesis, which sees the role of the immune system in checking the
normalcy of tissue architecture and communication. I propose that natural cooperation
exists side by side with natural selection, so that the immune system represents a search
engine for potential commensal microorganisms in addition to its defensive function.
Keywords: Immunity, function, theory, immunoregulation, Danger, Self-nonself,
Integrity, Pattern-recognition, homeostasis, commensal, symbiont, co-operativity,
rejection, protection, cancer, T-cells, B-cells, APC, DC, Treg.
INTRODUCTION
A hallmark of good preventive health care includes successful immune defenses
against many infectious diseases, and conversely a tolerance of an organ
transplant without affected immunity. Immunology as a science started as a wish
aimed to explain physiologic processes underlying the success of first

1
Faculty of Medicine, St. Petersburg State University, Russia and
2
Institute of
Endocrinology, I.I. Mechnikov North-Western State Medical University, Saint
Petersburg, Russia
Abstract: Autoimmunity and its contradictory nature in autopathokinesis have drawn
attention from the emergence of immunology as a science. The properties of antibodies
towards nuclear antigens of endocrine cells are both theoretically and clinically hot
topics as are their applications in the modulation of genetically determined cell
functions. In this chapter we discuss the history of physiological autoimmunity concept,
the difference and borders between physiological autoimmunity and pathological
autoallergy, regulatory potential of the first and pathogenic implications of the last one.
The review of our data on antibody production after immunization of animals with
some nuclear antigens is given, characterizing their properties and the mechanisms of
their intracellular penetration and association with nuclear targets. There are data on the
presence of similar autoantigens and corresponding autoantibodies in the blood sera of
intacts. The antibodies towards chromatin components appear to be able to penetrate
into the nuclei of the endocrine cells and act there through mechanism(s) different from
hormonal regulators, at least in adrenals. They stimulate or inhibit proliferation,
translation and transcription, hormone biosynthesis in target cells. This suggests that
autoimmunity is one of the mechanisms in the physiological regulation of cellular
morphogenesis and genetically determined functions. Physiological autoimmunity thus
contributes to the bringing-together and co-tuning of genetic information reading,
adaptive immune system is regarded as a tool for self-construction of multicellular
organism and for support of multicellularity. At the same time, however, the literature
on autoimmunity has mostly been concentrated on eliciting a particular disease only.
Special reconsideration of these statements is given, the concept of Immunacea is
coined, immunoneuroendocrine regulatory meta-system is reviewed, penetration of
antibodies into living cells is discussed, some aspects of fetal-maternal immune
relations are considered, and link of human microbiome to autoimmunity is
emphasized.
Keywords: Autoimmunity, autoallergy, counter-immune response,
endocrinopathies, immunoneuroendocrine meta-system, Immunacea, intracellular

*Address correspondence to Leonid P. Churilov: Department of Pathology, Faculty of Medicine, Saint
Petersburg State University; of.111, bld. 8a, 21
st
line, V.O., Saint Petersburg, 199034, Russia;
Tel: + 7 904 336 3017. E-mail: elpach@mail.ru
Send Orders of Reprints at reprints@benthamscince.net
Autoimmunity vs. Autoallergy Physiologic Autoimmunity and Preventive Medicine 73
penetration of antibodies, Hashimoto’s disease, marfanoid phenotype,
microbiome, pregmunity, prolactin, receptor-agonistic autoantibodies, self-
tolerance.
INTRODUCTION
Autoimmune response permanently attracted the attention of pathophysiologists
from the very first steps of Immunology because the phenomenon of
autoimmunity comprises in itself the key contradiction of Pathophysiology as a
science. Autoimmunity is the phenomenon brightly expressing the unity, mutual
penetration and relativity of injury and defense. It concentrates the idea of
autopathokinesis or disease self-driving due to imperfection of defense, which is
highly meaningful for the whole science of Pathology. The first autoimmune
endocrine disorder (struma lymphomatosa or chronic autoimmune thyroiditis -
AIT) was described by Hakaru Hashimoto 100 years ago, in 1912 [1]. To that
moment I.I. Mechnikov’s school already coined an idea of endocrine cell
regulation by means of antibodies (“cytotoxins”) [2-4].
FROM “PHYSIOLOGICAL INFLAMMATION” TO AUTOIMMUNE
SELF-REGULATION
Even until now in the world literature autoimmunity is often considered just as a
pathological mechanism able to elicit some kind of disease. For a long time,
practically, from the moment of its origination, the classical Immunology,
addressing to the problem of autoimmunity, was restrained with the principle of
«Horror autotoxicus», attributed to Paul Ehrlich and Julius Morgenroth [5]. This
concept claims that no antibodies can be formed against self components in a
healthy organism. Such a view was in contradiction with the evolutionary concept
of immunity, formulated by I.I. Mechnikov (1845-1916), who from the very
beginning of Immunology, interpreted the role and function of immune cells
much broader, then just responsibilities of gendarmes or border guards aimed
exclusively on the aliens. Contemporaries of Mechnikov, which co-authored with
him the essentials of new science, mostly microbiologists or immunochemists by
their interests, insisted on this “anti-alien” priority [6]. But as early as in 1892 I.I.
Mechnikov published small paper on the existence of Darwinian struggle “within
74 Physiologic Autoimmunity and Preventive Medicine Churilov et al.
a body”, i.e. between cellular elements of the same Metazoan organism [7].
According his idea, immunity and specialized cells, responsible for it, are
evolutionary required first of all not as warriors against aliens, but in order to keep
peace within own body of an individual, by means of harmonization of the
contradictions between elements of self. In this fruitful concept immune system
looks like product of inherent imperfection of the body and serves for permanent
self–construction and remodeling of multicellular self organism in ontogenesis, by
means of “physiological inflammation” or (as it was named later by I.I.
Mechnikov and his pupils) – “natural autoimmunity” (Fig. 1) [2, 7–8].
We feel some resemblance between this early Mechnikov’s idea and recent
concept of Integrity coined by Z. Dembić (see Chapter 2); especially regarding his
assumption that similar molecular signals regulate the response of immune cells
and establish intercellular assembly in multicellular tissues of Metazoa.

The Medical Research Center “Immunculus-Biotest”; P.K. Anokhin Institute of
Normal Physiology, Russian Academy of Medical Sciences, Moscow, Russia
Abstract: “…The initial paradigm “one autoantibody for one disease” does not appear
to be useful any longer. An autoantibody profile does seem to offer more diagnostic and
prognostic power than the determination of single autoantibody specificity” (P-L.
Meroni). Why is it so? Fruitfulness of the idea for identification of autoantibody
depends on reactivity patterns (autoantibody signatures or profiles) illustrated by
analyses of few examples where clinical and laboratory symptoms corresponded to
changes in profiles of serum auto-Abs and mismatched to single auto-Ab serum
evaluation. Author proposes that future “mapping” repertoires of thousands of natural
auto-Abs as the profiles will lead to the appearance of principally new technologies in
clinical as well as pre-clinical diagnosis of different chronic diseases.
Keywords: Natural autoimmunity, immune network, serum autoantibodies,
laboratory diagnostic, profiles of autoantibodies.
WHICH INFORMATION MAY BE OBTAINED FROM THE ANALYSIS
OF SERUM PROFILES OF AUTOANTIBODIES?
Evaluation of human autoantibodies (auto-Ab) with different antigen specificity
has been carried out around the world in a large number of clinical laboratories.
The specialized kits for an assessment of blood serum content of auto-Ab against
DNA, cardiolipin, beta2-glycoprotein I, collagen, thyroglobulin, etc., were
provided by dozens of companies. All commercially offered kits intended for
detection of separate auto-Ab in serum samples are considered as markers of
certain autoimmune diseases. However, our practice as well as observations of our
colleagues, indicate that this approach may be ground for incorrect clinical
conclusions. The serum auto-Abs investigated in patients with immunodeficiency

*Address correspondence to Leonid P. Churilov: Department of Pathology, Faculty of Medicine, Saint
Petersburg State University; of.111, bld. 8a, 21
st
line, V.O., Saint Petersburg, 199034, Russia; Tel: +
7 904 336 3017; E-mail: elpach@mail.ru
Send Orders of Reprints at reprints@benthamscince.net
Autoimmune Thyroiditis Physiologic Autoimmunity and Preventive Medicine 209
were Haitians, homosexuals, hemophiliacs and heroin addicts only) [1].
Autoimmune thyroiditis (AIT) can be regarded as the unique non-infectious
example of this kind, described as a rare endemic thyroid ailment 100 years ago
[2], and nowadays appeared to be, probably, most universally spread human auto-
allergic disease, one of the most acute problems for preventive medicine.
Centenary of Hashimoto’s Disease
The very first proven antibody-mediated auto-allergic human disorder was
described just 8 years before AIT [3]. To that moment the concepts of humoral
and cellular immunity were newborn, a role of plasma cells, recently found by
P.G. Unna [4], as a source of antibodies was not known, the existence of T-
lymphocytes was not even supposed. At the same time, an outstanding Russian
pathophysiologist, many times credited above (see Chapter 4) – Ye.S. London
(1904) already suggested the unitary theory of humoral and cellular immunity,
postulating that both have the same source [5]. Thyroidology to that moment
already had like 75 years of development passed as an area of clinical medicine,
but absolutely irrelevant to Immunology. Diffuse toxic goiter was known [6] and
related to nervous disorders, although more than half a century still had to pass
before the future discovery of thyroid-stimulating antibodies [7]. Thanks to
research of newly (1909) Nobel-crowned E. Th. Kocher, the concept of iodine-
deficient etiology of endemic goiter, earlier suggested by G.A. Chatin, has got a
broad recognition [8, 9]. But the pathologists knew colloid goiter only, resulted
from thyroid hyperplasia in lack of iodine. Yet, goiter was common in some areas,
where iodine deficit could not exist at all: for example, on Kyushu island of
Japan, famous for the birthplaces of iodine-containing mineral deposits and for
seafood attraction of its inhabitants.
A young surgeon, Hakaru Hashimoto (1881-1934) together with Prof. Sakurai
(histologist) and Prof. Nakayama (pathologist) during 1907-1910 took part in
pathohistological studies of partially removed thyroid glands. Hakaru was medical
doctor in 3
rd
generation (Fig. 1), the first graduate from recently established
Kyushu Imperial University at Fukuoka and clinical resident of the first Japanese
neurosurgeon, pupil of Jan Mikulicz-Radecky, Hayari Miyake (1867-1945).
210 Physiologic Autoimmunity and Preventive Medicine Churilov et al.